As an increased product of high-rate aerobic glycolysis in tumors, lactate could regulate the immunosuppressive tumor microenvironment (TME). A PEG-CDM surface modified, GSH-dependent responsive hollow mesoporous organosilica nanoplatform loaded with hydroxycamptothecin (HCPT) and siMCT-4 was administrated for synergistic tumor chemo-immunotherapy. The nanoplatform cascaded responded to the weak acid TME and the high level of GSH in tumor cells. HCPT and siMCT-4 were continuously released from the nanoplatform for chemotherapy and inhibiting intracellular lactate efflux. The increased intracellular lactate and HCPT effectively induced tumor cell apoptosis. Moreover, the decreased extracellular lactate polarized tumor-associated macrophages (TAMs) phenotype from M2 type to M1 type and restored CD8 + T cell activity in vivo. The results demonstrated that the nanoplatform effectively removed the immunosuppressive TME, inhibited tumor growth, and suppressed lung metastasis of B16F10 cells and 4T1 cells via the combination of inhibiting lactate efflux and chemotherapy. Accordingly, it suggested a strategy to transform immunosuppressive tumors into "hot" tumors and inhibit the tumor growth with high efficiency in vivo.

Ferroptosis is a recently discovered route of regulated cell death that offers the opportunities for the treatment of chemotherapy-resistant tumor indications, but its efficacy can be affected by the glutathione peroxidase 4 (GPX4) and ferroptosis suppressor protein 1 (FSP1) antioxidant mechanisms, posing significant challenges for its clinical translation. In this study, we report a Cu-tetra­(4-carboxyphenyl)­porphyrin chloride­(Fe­(III)) (Cu-TCPP­(Fe)) metal organic framework (MOF)-based nanosystem for the efficient incorporation of Au nanoparticles (NPs) and RSL3, which can demonstrate enzyme-like activities to universally suppress the antiferroptotic pathways in tumor cells for amplifying ferroptotic damage. Herein, Cu-TCPP­(Fe) MOF nanosheets were integrated with Au NPs via in situ nucleation and loaded with RSL3 via π–π stacking, which were eventually modified with polyethylene glycol (PEG) and iRGD for tumor-targeted drug delivery. Specifically, the Au NPs can demonstrate glucose oxidase-like activities for efficient glucose depletion, thus disrupting the pentose phosphate pathway to impede reduced glutathione (GSH) biosynthesis and prevent the recycling of coenzyme Q10 (CoQ10) to CoQ10H2, while Cu species can oxidize GSH into oxidized glutathione (GSSG). These nanocatalytic activities can lead to the simultaneous inhibition of the GPX4/GSH and FSP1/CoQ10H2 pathways and cooperate with the GPX4-deactivating function of RSL3 to cause pronounced ferroptotic damage, thereby providing a strong rationale for the application of ferroptosis therapy in the clinic.

PHNPs and 3-MA re-polarize TAMs to M1-type by activating the protein of NF-κB p65 and then remodelling the immunosuppressive microenvironment, thus activating immune response and inhibiting tumor growth.

incidences are increasing year by year. [2] As a newly discovered regulatory cell death, ferroptosis is a type of cell death caused by iron-dependent accumulation of lipid peroxides. [3][4][5] As we all known, normal liver is the important organ to store and metabolize iron. [6] Thus, inducing ferroptosis of liver tumor cells may be a new direction for specific treatment of liver tumors. Unfortunately, Sorafenib is currently the only anti-tumor chemotherapy drug that can treat liver tumors by inducing ferroptosis in clinical, but its drug resistance greatly affects the therapeutic effect. [7,8] Therefore, it is urgent to exploit novel strategies to induce ferroptosis in liver tumors.Briefly, ferroptosis is mainly induced in two modes: One is the classic ferroptosis induction mode, which destroys the membrane protective mechanism of tumor cells to activate ferroptosis by which is mainly managed by the GPX4 pathway. [9,10] GPX4 protein is considered the only glutathione peroxidase (GPXs) family molecule that protects biofilms from hydroperoxidation. [11] There are two main therapeutic methods targeting GPX4 pathway for inducing ferroptosis. The first one is the inactivation and depletion of GPX4 protein. [12] For example, (1S,3R)-RSL3 (RSL3) can covalently bind to the active site of GPX4, thereby mediating ferroptosis regulated by GPX4. [13,14] The second approach is to consume intracellular GSH content. [15] Reduced glutathione, a tripeptide form of antioxidant, can act as a synergistic molecule of GPX4 and assist GPX4 to eliminate lipid ROS. [16,17] Many nanomaterials with the ability to consume GSH have been demonstrated to activate ferroptosis, which provide additional strategies for inducing ferroptosis. [18][19][20] Cu(II) has been widely used for its excellent GSH consumption capacity. [21] Furthermore, another way to induce ferroptosis is named as nonclassical ferroptosis induction mode. Basically, the nonclassical mode is initiated by increasing the Fe 2+ content in tumor cells. [22] For instance, excessive activation of HMOX1 protein, down-regulated ferroportin expression and up-regulated transferrin expression could lead to overload Fe 2+ in tumor cells. [23][24][25] Some exogenous ironcontaining substances (hemin, FeCl 2 , and (NH 4 ) 2 Fe(SO 4 ) 2 ) can cause intracellular iron overloading, which can effectively Liver tumor is difficult to cure for its high degree of malignancy and rapid progression characteristics. Ferroptosis as a new model of inducing cell death is expected to break the treatment bottleneck of liver tumors. Here, a strategy to induce ferroptosis in HepG2 cells with acid-degradable tumor targeted nanosheets Cu-Hemin-PEG-Lactose acid (Cu-Hemin-PEG-LA) is proposed. After highly ingested by HepG2 cells, Cu-Hemin-PEG-LA nanosheets are degraded by weak acid and release Cu(II) and hemin, which consuming intracellular glutathione (GSH) content and increasing the expression of heme oxygenase 1 (HMOX1) protein, respectively. Furthermore, the expression of glutathione peroxidase 4 protein (GPX...